The GDNF family of neurotrophic factors includes four members: glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin (PSPN). GDNF family ligands signal through receptors consisting of a GPI-linked GFRα subunit and the transmembrane receptor tyrosine kinase RET. In order to activate the transmembrane receptor tyrosine kinase Ret, each of the GDNF family neurotrophic factors binds preferentially to one of the glycosyl-phosphatidylinositol (GPI)-linked GDNF family α-receptors (GFRα1-4) (Airaksinen et al., 1999). GFRα4, the preferential receptor for persephin (PSPN), has so far been described only from chicken (Enokido et al., 1998; Thompson et al., 1998). GDNF signals via GFRα1, neurturin via GFRα2, artemin via GFRα3, whereas the mammalian GFRα receptor for persephin (PSPN) and the biological role of GFRα4 has so far remained unclear.
RET-mutations are known to be related with inherited cancer syndrome (MEN2), characterized by medullary thyroid carcinoma (MTC) and with sporadic forms of MTC and pheochromocytoma, but it is not clear why different specific RET mutations associate with the different disease phenotypes, for example, why hyperparathyroidism and familial MTC associate with certain types of mutations whereas sporadic MTC is associated with other types of mutations. For example Ret is expressed in malignant thyroid C-cells and adrenal chromaffin cells but also in normal cells non-affected in MEN2, leaving the cause for the cell specificity of the MEN2 cancer syndrome unclear.
Studies of expression and splicing patterns with mouse and human GFRα4, surprisingly provided a response to the previous unclarities.